title: Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism.
abstract: OBJECTIVE
  To examine the role of both protein kinase C (PKC)-β and vascular endothelial growth factor receptor (VEGFR)-2 in malignant pleural mesothelioma (MPM) using respective inhibitors, enzastaurin and KRN633.
  
  
  METHODS
  MPM cell lines, control cells, and a variety of archived MPM tumor samples were used to determine the protein expression levels of PKC-β, VEGFR-2, VEGF, and p-AKT. Effects of enzastaurin and KRN633 on phosphorylation status of key signaling molecules and viability of the mesothelioma cells were determined. The common soil nematode, Caenorhabditis elegans, was treated with enzastaurin to determine its suitability to screen for highly potent kinase inhibitors.
  
  
  RESULTS
  PKC-β1, PKC-β2 and VEGFR-2/KDR were overexpressed in MPM cell lines and MPM tumor tissues. Enzastaurin treatment resulted in significant loss in viability of VEGF induced cell proliferation; however, the effect of KRN633 was much less. Enzastaurin also dramatically decreased the phosphorylation of PKC-β, its downstream target p-AKT, and surprisingly, the upstream VEGFR-2. The combination of the two drugs at best was additive and similar results were obtained with respect to cell viability. Treatment of C. elegans with enzastaurin resulted in clear phenotypic changes and the worms were hypermotile with abnormal pattern and shape of eggs, suggesting altered fecundity.
  
  
  CONCLUSIONS
  PKC-β1 and VEGFR-2 are both excellent therapeutic targets in MPM. Enzastaurin was better at killing MPM cells than KRN633 and the combination lacked synergy. In addition, we show here that C. elegans can be used to screen for the next generation inhibitors as treatment with enzastaurin resulted in clear phenotypic changes that could be assayed.
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Loganathan
authors.forename: Rajani
authors.initials: R
authors.lastname: Kanteti
authors.forename: Shahid S
authors.initials: SS
authors.lastname: Siddiqui
authors.forename: Essam
authors.initials: E
authors.lastname: El-Hashani
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Hari
authors.initials: H
authors.lastname: Vigneswaran
authors.forename: Gustavo
authors.initials: G
authors.lastname: Cervantes
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Aliya N
authors.initials: AN
authors.lastname: Husain
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia